title: The effects of Dickkopf-4 on the proliferation, differentiation, and apoptosis of osteoblasts.
abstract: The Dickkopf family of proteins is comprised of four members (Dkk1, Dkk2, Dkk3, Dkk4) that are known to modulate Wnt/β-catenin signaling, which is activated during bone formation. Although the effects of Dkk1 on Wnt/β-catenin signaling have been well studied, little is known about the effects of Dkk4. Therefore, to evaluate the role of Dkk4 in osteoblastogenesis, we used the mouse osteoblastic cell line MC3T3-E1, in which Dkk4 expression was suppressed by small interfering RNA knockdown. Our results showed that the suppression of Dkk4 expression promoted osteoblast proliferation and differentiation and suppressed apoptosis. In colony-forming unit alkaline phosphatase assay, Dkk4 knockdown cells possessed markedly higher alkaline phosphatase activity compared with Dkk1 knockdown cells. Reduced Dkk4 expression also led to the up-regulation of β-catenin levels, β-catenin/T cell factor activity, and Wnt-target genes. In contrast, overexpression of Dkk4 in MC3T3-E1 cells led to inhibition of osteoblast differentiation. Our findings reveal that Dkk4 functions as an inhibitor of osteoblastogenesis through Wnt/β-catenin signaling, providing new insights into the relationship between Wnt/β-catenin signaling and Dkk4 in bone formation.
authors.affiliation: MD, PhD, Department of Women's Health, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo, Tokyo 113-8510, Japan. teragyne@tmd.ac.jp.
authors.forename: Shiro
authors.initials: S
authors.lastname: Hiramitsu
authors.forename: Masakazu
authors.initials: M
authors.lastname: Terauchi
authors.forename: Toshiro
authors.initials: T
authors.lastname: Kubota
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D005786:Gene Expression Regulation / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C513131:Dkk4 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin